1. Field of the Invention
The present invention is directed at a process for the oxidation of alcohols using homogeneously soluble polymer-enlarged nitrogen compounds as catalysts. In particular, the invention relates to a process where the catalysts used are compounds that can be obtained by polymerization of a mixture containing
(i): 0.1-100, preferably 1-20 wt. -% of a compound (I) 
(ii): 0-99.9, preferably 80-99 wt. -% (meth)acrylic acid ester,
(iii): 0-80, preferably 1-20 wt. -% other xcex1,xcex2-unsaturated compounds, other than i) wherein A is a ring with 5 to 8 elements, which in addition to one nitrogen can have 0-3 other hetero atoms, such as N, O, S, and which in addition to the substituents shown in the formula can have 0-3 other radicals, such as (C1-C8)-alkyl, (C1-C8)-alkoxy, halogens, wherein R1, R2, R3, R4 are, independent of each other, (C1-C8)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C8)-cycloalkyl, or R1 and R2 and/or R3 and R4 or R1 and R3 and/or R2 and R4 are connected with one another via a (C2-C8)-alkylene bridge, wherein R5 is H or methyl, X is O, NH, NR1, and wherein Y is xc2x7 or H, such as HEMA or EGDMA. It is understood that all subranges and numbers within the above discussed ranges are present as if explicitly written out.
In organic synthesis, the oxidation of alcohols represents an important transformation for obtaining aldehydes, ketones, or acids. These in turn are advantageously suitable, if they are not themselves intended as the target molecule, for further reaction to produce successor products, since they are very easily accessible to nucleophilic addition reactions. They therefore frequently play a key role specifically in the technical production of bioactive molecules, as part of the synthesis path.
The oxidation of secondary and primary alcohols to produce aldehydes and ketones with N-oxygen compounds of 2,2,6,6-tetramethyl-4-piperidine (TEMPO) in the presence of oxidants such as m-CPBA, hypochlorite/bromite solution, or K3Fe(CN)6 has been known for a long time (J. Org. Chem. 1987, 52, 2559-62; ibid. 1975, 40, 1860; Synthesis 1966, 1153). Furthermore, polymer-enlarged TEMPO radicals already have been synthesized with the purpose of working them into polymer mixtures as UV stabilizers (DE 2748362; L. Wenzhong, Polym. Degra. and Stab. 1991, 31, 353-364).
Endo et al. used partially soluble polymer-enlarged TEMPO compounds in alcohol oxidation reactions, among other substances (Journal of Polymer Science: Polymer Chemistry Edition, Vol. 23, 2487-94 (1985)). However, it was shown that the insoluble oxidation catalysts of the type introduced there were better.
An object of the present invention is to provide a process for the oxidation of alcohols in the presence of oxidation catalysts, on the basis of homogeneously soluble polymer-enlarged nitrogen compounds. In particular, this process is usable on a technical scale, in other words advantageous with regard to the aspects of economics and ecology.
Because an oxidation agent and catalytic amounts of homogeneously soluble polymer-enlarged nitroxyl derivatives are used in a process for the oxidation of alcohols, where these derivatives are obtained by copolymerization of a mixture containing
(i): 0.1-100, preferably 1-20 wt. -%, including 3, 5, 10 and 15 wt. % and all weights percent between all stated values of a compound (I) 
where Yxe2x95x90xc2x7or H,
A is a ring with 5 to 8 elements, which in addition to one nitrogen can have 0-3 other hetero atoms, such as N, O, S, and which in addition to the substituents shown in the formula can have 0-3 other radicals, such as (C1-C8)-alkyl, (C1-C8)-alkoxy, halogens, R1, R2, R3, R4 are, independent of each other, (C1-C8)-alkyl, (C6-C18)-aryl, (C7-C19)-aralkyl, (C3-C8)-cycloalkyl, or R1 and R2 and/or R3 and R4 or R1 and R3 and/or R2 and R4 are connected with one another via a (C2-C8)-alkylene bridge, R5 is H or methyl, X is O, NH, NR1, and wherein Y is the 0-3 other radicals or H.
(ii): 0-99.9, including 5, 10, 20, 30, 40, 50, 60, 70, 80, and 90 and all weights percent between all stated values, preferably 80-99 wt. -% (meth)acrylic acid ester,
(iii): 0-80, including 5, 10, 20, 30, 40, 50, 60 and 70 and all weights percent between all stated values, preferably 1-20 wt. -% other xcex1,xcex2-unsaturated compounds, such as HEMA or EGDMA, the desired alcohol oxidation products, preferably the aldehydes and ketones, are obtained in a surprisingly simple and cost-effective manner. According to the invention, the oxidation reaction is completed within a few minutes, and the mixture can be processed. The catalyst can be removed and reused, and the yields of oxidation product are almost quantitative. Because the catalyst can be reused, the synthesis costs can be kept low.
It is understood that xc2x7 signifies a radical electron in the context of this invention.
In a preferred embodiment, the radicals R1xe2x88x92R4xe2x95x90methyl, R5xe2x95x90methyl or H, Xxe2x95x90O, NH, where A represents a piperidine ring.
A process where the polymer-enlarged nitroxyl derivative with the formula (II) 
with a ratio of n/m of 1-100, preferably 1-50, and an average molecular weight of 1-200 kDa, preferably 10-100 kDa, is used, is especially preferred.
Other xcex1,xcex2-unsaturated compounds of Type iii that can be used are particularly those monomers that help to change the solubility properties of the polymer, i.e. ideally adapt it to the solvent system to be used. These monomers furthermore can have a crosslinking effect. This has the result that individual polymer strands are connected with one another, which in turn can have a significant influence on the solubility properties and the secondary structure of the polymer backbone and thereby indirectly on the reactivity of the catalyst. Other compounds that can be used are preferably the monomers of component i) and ii) of the polymerizate iii) in DE 19734360. The use of HEMA or EGDMA is very especially preferred in this regard.
In principle, the substances that a person skilled in the art would consider for use for this reaction can be used as oxidation agents. Preferably, these are K3Fe(CN)3 or aqueous NaOCl solution. Aqueous NaOCl solution is preferred, since it is less expensive and does not result in any cyanide problems, especially on a large technical scale.
The oxidation according to the invention is fundamentally conducted in accordance with that using monomer TEMPO, preferably in a two-phase system of organic and aqueous solvents. Ethyl acetate, acetonitrile, dichloromethane, or benzonitrile can serve as preferred organic solvents. Ethyl acetate and acetonitrile are very especially preferred.
The oxidation agent, the polymer-enlarged nitroxyl derivative of Formula (I), preferably that of Formula (II), is dissolved in the selected two-phase system. In the aqueous phase, the pH is adjusted in such a way that oxidation takes place at a pH of 6-13, preferably 9-10. Preferably, sodium carbonate is used to adjust the pH. However, any of the bases that a person skilled in the art would use for this purpose can be used, such as potassium carbonate, sodium hydrogen carbonate, sodium hydrogen phosphate, for example. Subsequently, the alcohol can be added to the mixture. The reaction is quantitatively completed in a few minutes.
The reaction is preferably carried out at temperatures from xe2x88x9220xc2x0 C.-80xc2x0 C., preferably 0-30xc2x0 C. After completion of the reaction, it can be processed using methods known to a person skilled in the art.
If work is carried out using a two-phase system, the phase that contains organic product and possibly catalyst is separated from the aqueous phase. A special advantage of the process according to the invention is that the polymer-enlarged catalyst can easily be recovered from the organic phase after the reaction is complete, and is therefore available for another oxidation cycle. This can be done using filtration by means of an ultrafiltration/nanofiltration membrane, or by means of precipitation by adding suitable solvents, preferably alcohols such as methanol or ethanol, petroleum ether, hexane, or diethyl ether.
However, the use of the process in a membrane reactor is especially preferred. In this way, the synthesis processes that are normally carried out using the batch process can take place quasi-continuously or continuously, and this appears to be particularly advantageous for a technical process, from a cost aspect. The use of the process according to the invention in a membrane reactor takes place analogous to the process described in the state of the art (T. Mizller, J. Mol. Cat. A: Chem. 1997, 116, 39-42; DE 199 10 691.6; Wandrey et al., Tetrahedron Asymmetry 1999, 10, 923-928). In this connection, the membrane reactor can act as a cross-flow filtration module or a dead-end filtration module (DE 19947505.9 as well as DE 19910691.6 or xe2x80x9cEngineering processes for Bioseparations,xe2x80x9d edited by: Laurence R. Weatherley, pages: 135-165; Butterworth-Heinemann, 1994; ISBN: 0 7506 1936 8).
Another aspect of the invention deals with the use of the oxidation products produced according to the invention in organic synthesis, preferably for the production of bioactive compounds.
The present process allows simple oxidation of alcohols to produce the corresponding desired derivatives, which can be well carried out on a technical scale. In this connection, the reaction times that result are surprisingly short, as compared with the known insoluble polymer-enlarged species. This, and the fact that the catalyst can be easily recycled and reused, are the reasons why the claimed process is very well suited for technical use. Furthermore, excellent selectivity in favor of primary alcohols is found if both primary and secondary alcohols are present in the substrate or in the reaction mixture.
The following are understood to be (C1-C8)alkyl: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, or octyl, as well as all bond isomers.
A (C6-C18)-aryl radical is understood to be an aromatic radical with 6 to 18 C atoms. In particular, this includes compounds such as phenyl, napththyl, anthryl, phenanthryl, biphenyl radicals. These can be substituted with (C1-C8)-alkoxy, (C1-C8)-haloalkyl, OH, Cl, NH2, NO2, where single and multiple substitution is possible. In addition, the radical can have one or more hetero atoms such as N, O, S.
(C1-C8)-alkoxy is a (C1-C8)-alkyl radical bound to the molecule in question via an oxygen atom.
A (C7-C19)-aralkyl radical is a (C6-C18)-aryl radical bound via a (C1-C18)-alkyl radical.
Within the scope of the invention, the term acrylate is also understood to mean the term methacrylate.
(C1-C8)-haloalkyl is a (C1-C8)-alkyl radical substituted with one or more halogen atoms. Chlorine and fluorine are halogen atoms that come into particular consideration. The term (C2-C8)-alkylene chain is understood to mean a (C2-C8)-alkyl radical that is bound to the molecule in question via two different C atoms. It can be substituted with (C1-C8)-alkoxy, (C1-C8)-haloalkyl, OH, halogen, NH2, NO2, SH, Sxe2x80x94(C1-C8)-alkyl, where single and multiple substitution is possible.
(C3-C8)-cycloalkyl is understood to mean cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl radicals. Halogen is fluorine, chlorine, bromine, iodine.
Within the scope of the invention, a membrane reactor is understood to mean any reaction container where the catalyst is enclosed in a reactor, while substances with a low molecular weight are passed to the reactor or can leave it. In this connection, the membrane can be directly integrated into the reaction space, or be built into a separate filtration module outside of it, where the reaction solution flows through the filtration module continuously or intermittently, and the retentate is passed into the reactor. Suitable embodiments are described in W098/22415 and in Wandrey et al. in Jahrbuch [Yearbook] 1998, Verfahrenstechnik and Chemieingenieurwesen [Process Technology and Chemical Engineering], VDI p. 151 ff.; Wandrey et al. in Applied Homogeneous Catalysis with Organometallic Compounds, Vol. 2, VCH 1996, p. 832 ff.; Kragl et al., Angew. Chem. 1996, 6, 684 f., among other references.